Improved synthesis of 4-/6-substituted 2-carboxy-1H-indole-3-propionic acid derivatives and structure-activity relationships as GPR17 agonists

Younis Baqi, Samer Alshaibani, Kirsten Ritter, Aliaa Abdelrahman, Andreas Spinrath, Evi Kostenis, Christa E. Müller

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The orphan G protein-coupled receptor GPR17 was shown to be involved in myelin repair and has been proposed as a novel drug target for the treatment of brain and spinal cord injury and for multiple sclerosis. Recently, 3-(2-carboxy-4,6-dichloro-indol-3-yl)propionic acid (MDL29,951, 1a) was discovered and characterized as a potent synthetic GPR17 agonist. In the present study we substantially optimized the preparation of 1a, which is carried out via Japp-Klingemann condensation of 3,5-dichlorophenyldiazonium chloride and deprotonated 2-(ethoxycarbonyl)cyclopentanone yielding phenylhydrazone derivative 5a followed by Fischer indole (diaza-Cope) rearrangement. A robust synthesis of 1a (75% yield) was developed to allow upscaling of the procedure. The developed method was applied to the synthesis of a series of 10 derivatives, eight of which represent new compounds. Biological evaluation in calcium mobilization assays using 1321N1-astrocytoma cells recombinantly expressing the human GPR17 provided first insights into their structure-activity relationships. 3-(2-Carboxy-4,6-dibromo-indol-3-yl)propionic acid (1b) showed similar potency to 1a and represents the most potent synthetic GPR17 agonist described to date with an EC50 value of 202 nM.

Original languageEnglish
Pages (from-to)86-92
Number of pages7
JournalMedChemComm
Volume5
Issue number1
DOIs
Publication statusPublished - 2014

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Propionates
Structure-Activity Relationship
Derivatives
Astrocytoma
Myelin Sheath
G-Protein-Coupled Receptors
Spinal Cord Injuries
Multiple Sclerosis
Chlorides
Condensation
Assays
Brain
Repair
Calcium
Pharmaceutical Preparations
indole
propionic acid
cyclopentanone
phenylhydrazone
2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Improved synthesis of 4-/6-substituted 2-carboxy-1H-indole-3-propionic acid derivatives and structure-activity relationships as GPR17 agonists. / Baqi, Younis; Alshaibani, Samer; Ritter, Kirsten; Abdelrahman, Aliaa; Spinrath, Andreas; Kostenis, Evi; Müller, Christa E.

In: MedChemComm, Vol. 5, No. 1, 2014, p. 86-92.

Research output: Contribution to journalArticle

Baqi, Younis ; Alshaibani, Samer ; Ritter, Kirsten ; Abdelrahman, Aliaa ; Spinrath, Andreas ; Kostenis, Evi ; Müller, Christa E. / Improved synthesis of 4-/6-substituted 2-carboxy-1H-indole-3-propionic acid derivatives and structure-activity relationships as GPR17 agonists. In: MedChemComm. 2014 ; Vol. 5, No. 1. pp. 86-92.
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